Pancreatic cancer has one of the highest mortality rates among all cancers and is the fourth most common cause of adult cancer death in the United States with an estimated 42,470 cases per year. See Nieto et al., The Oncologist, 13:562-576 (2008); and Cancer Facts and Figures, American Cancer Society (2009). It accounts for about 3% of all newly diagnosed cancers in the United States each year. However, almost double that number cancer patients, about 6%, die from pancreatic cancer. See Cancer Facts and Figures, American Cancer Society (2009). The high mortality rate from pancreatic cancer is a result of the high incidence of metastatic disease at the time of diagnosis. As a result, only 5%-15% of patients are candidates present with tumors are amenable to resection. See Nieto et al, The Oncologist, 13:562-576 (2008).
The standard first-line treatment for treating pancreatic cancer is gemcitabine (e.g., GEMZAR®), which was approved by the Food and Drug Administration (“FDA”) in 1996. In a clinical study with 126 patients with locally advanced pancreatic cancer (63 treated with gemcitabine), gemcitabine was shown to be superior to 5-fluororuracil (5-FU) in terms of median overall survival (5.7 months for gemcitabine versus 4.2 months for 5-FU), median time to disease progression (2.1 months for gemcitabine versus 0.9 months for 5-FU), and clinical benefit responses. However, although gemcitabine has become a standard palliative therapy for treating pancreatic cancer since its approval in 1996, there has been little improvement in pancreatic cancer treatment. For all stages of pancreatic cancer combined, the 5-year relative survival rate for pancreatic cancer between 1996 and 2004 was 5%, drastically lower than survival rates for other cancers. See American Cancer Society, Surveillance and Health Policy Research (2009).
Multiple studies have been conducted but failed to identify an improved therapeutic regime for treating pancreatic cancer by combining gemcitabine with a second agent. The only exception to the failed attempts to identify effective combination therapy regime was the combination of gemcitabine and erlotinib (e.g., TARCEVA®). See Moore et al., J. Clin. Oncol. 25:1960-1966 (2007). The gemcitabine/erlotinib combination improved the median overall survival (6.4 months versus 6.0 months) and median progression free survival (3.8 months versus 3.5 months) over gemcitabine monotherapy. See id. Based on this very modest improvement in overall survival and progression free survival (0.4 and 0.3 months, respectively), the FDA approved the gemcitabine/erlotinib combination in 2005. Despite its approval, the gemcitabine/erlotinib combination has not been widely used as a standard of care for treating pancreatic cancer because of side effects associated with the gemcitabine/erlotinib combination and the minimal improvement on survival over gemcitabine monotherapy. See Nieto et al., The Oncologist, 13:562-576 (2008).
To date, no standard guidelines for second-line treatment of pancreatic cancer have been established. Data supporting the use of second-line therapy compared to best supportive care is lacking. Benefits of second-line therapy seems to be modest, at the cost of drug toxicity. Almhanna et al., 2008, Oncology, Vol. 22, No. 10.
Taxanes have been investigated as a second-line treatment in gemcitabine-resistant pancreatic cancer patients. In a small study, weekly paclitaxel treatment in 18 patients with recurrent disease produced a response rate of 6% and a median overall survival of 17.5 weeks. Almhanna et al., Oncology, 22:10 (2008). In two small studies using a combination of docetaxel and gefitinib, the median overall survival was about 12 weeks. Capecitabine was also combined with docetaxel, with response rates ranging from 1% to 12% and a median overall survival of 13 weeks. In a study of 15 patients, the combination of docetaxel with mitomycin and irinotecan produced no response and the median overall survival was 24 weeks. Clinical benefits were not reported in any of these studies. Almhanna et al., Oncology, 22:10 (2008).
Albumin bound paclitaxel (e.g., ABRAXANE®) in combination with gemcitabine was found to be well tolerated in advanced pancreatic cancer in a Phase I/II study and showed evidence of antitumor activity. See, for example, US Patent App.; No. 2006/0263434; Maitra et al., Mol. Cancer Ther. 8(12 Suppl):C246 (2009); Loehr et al., J. of Clinical Oncology 27(15S)(May 20 Supplement):200, Abstract No. 4526 (2009); Von Hoff et al., J. of Clinical Oncology 27(15S)(May 20 Supplement), Abstract No. 4525 (2009); and Kim et al., Proc. Amer. Assoc. Cancer Res., 46, Abstract No. 1440 (2005).
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